1. Field of the Invention
The present invention relates to a suspendible composition comprising fine particles of a tricyclic compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable surfactant. The suspendible composition according to the present invention is useful as an orally administrable agent or eye drops.
2. Prior Art
Tricyclic compounds as shown by the below-mentioned general formula (I) and pharmaceutically acceptable salts thereof used in this invention have been known to possess excellent pharmacological activities such as immunosuppressive activity and antimicrobial activity, thereby useful for treating and/or preventing rejection against organs or tissue transplantation, graft versus host reaction, various autoimmune diseases and infectious diseases (Japanese Laid-Open Patent Application No. 61(1986)-148181, EP-A-0323042).
Particularly, FR 900506 substance which equals to FK 506 substance, FR 900520 substance, FR 900523 substance and FR 900525 substance are produced by fermenting Genus streptomyces, in particular, Streptomyces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces hygroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928). Particularly, FK 506 substance represented by the following formula possesses excellent immunosuppressive activity, thus useful for treating and/or preventing rejection against organs transplantation and diseases in the ophthalmology.
FK 506 substance: ##STR1## Chemical name: 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylviny l]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3. 1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone. PA0 and further, R.sup.2 is an alkyl group; PA0 R.sup.7 is a hydrogen atom, a hydroxy group, a protected hydroxy group or an alkoxy group, or an oxo group together with R.sup.1 ; PA0 R.sup.8 and R.sup.9 each is independently a hydrogen atom or a hydroxy group; PA0 R.sup.10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups or an alkyl group substituted by an oxo group; PA0 X.sup.1 is a hydrogen atom or a hydroxy group; PA0 X.sup.2 is a hydrogen atom; or PA0 X.sup.1 and X.sup.2 may together represent an oxo group or --CH.sub.2 O--; PA0 Y.sup.1 is a hydrogen atom or a hydroxy group; PA0 Y.sup.2 is a hydrogen atom; or PA0 Y.sup.1 and Y.sup.2 may together represent an oxo group, N--NR.sup.11 R.sup.12 or N--OR.sup.13 ; PA0 R.sup.11 and R.sup.12 each is independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group; PA0 R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, R.sup.22 and R.sup.23 each is independently a hydrogen atom or an alkyl group; PA0 R.sup.20 and R.sup.21 each is an oxo group or independently (R.sup.20 a and a hydrogen atom) or (R.sup.21 a and a hydrogen atom) in which R.sup.20 a and R.sup.21 a each independently is a hydroxy group, an alkoxy group or a group represented by the formula --OCH.sub.2 OCH.sub.2 CH.sub.2 OCH.sub.3, or R.sup.21 a is a protected hydroxy group, or R.sup.20 a and R.sup.21 a may together represent an oxygen atom in an epoxide ring; PA0 n is an integer of 1, 2 or 3; PA0 in addition to their above definitions, four of y.sup.1, y.sup.2, R.sup.10 and R.sup.23, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkyl substituted by one or more hydroxy, an alkoxy, benzyl and a group of the formula --CH.sub.2 Se(C.sub.6 H.sub.5); PA0 or a pharmaceutically acceptable salt thereof, said fine particles of the tricyclic compound and its pharmaceutically acceptable salt having the average size of 5 .mu.m or below; and a pharmaceutically acceptable surfactant, and optionally an aqueous medium. PA0 A. Ether type PA0 B. Ether-ester type PA0 C. Ester type
Injections or capsules for oral use of the tricyclic compound (I) have already been studied. The capsules are generally desirable preparation than the injections from the viewpoint of convenience, but would be difficult to slightly adjust an administration amount of active ingredient and also is not so easy to use for children. Thus, there is a demand for the development of liquid formulations which are excellent in absorption ability when administered orally.
When the tricyclic compound (I) of the present invention is employed in ophthalmology, a concern is caused about the appearance of systemic adverse effect upon its oral administration, intramuscular injection or intravenous injection. Accordingly, eye drops for local administration are preferable in ophthalmology as a formulation capable of reducing the appearance of the adverse effect and attaining the desired object with less administration amount.
The tricyclic compound (I) of the present invention is well-soluble in organic solvents and fats and fatty oils, whereas it is very slightly soluble in water. Therefore, the tricyclic compound (I) is made into oily eye drops or ophthalmic ointments, similar to the general slightly soluble agents, to be used in ophthalmology. However, the oily eye drops or ophthalmic ointments of the compound (I) are disadvantageous in that the tricyclic compound (I) is remarkably poor in penetration into ocular tissues and additionally are accompanied with evanescent paropsia or unpleasantness, thus unpractical.
Consequently, there has arisen a strong demand for the development of eye drops comprising the tricyclic compound (I) and having improvements in penetration into ocular tissues and in the aforesaid drawbacks.